The recent recognition that symptoms of behavioral depression form an integral component of the sickness response to many infectious and inflammatory conditions expanded views on the powerful influence of the immune system on the brain. It is now clear that immune activation not only contributes to classic host defense responses, such as fever, but also modulates cognitive and affective states. Whereas studies using the neuronal activation marker c-Fos have identified a constellation of brain nuclei that respond to immune activation, the roles that any of these regions play in the induction of sickness-induced behavioral depression remains undetermined. Our preliminary studies have shown that treatment with an immune stimulant suppresses behavior-related activation of forebrain nuclei associated with arousal, attention and memory, which may underlie the behavioral effects of immune activation. We have also shown that inactivation of the dorsal vagal complex in the brainstem blocks symptoms of behavioral depression and rescues behaviorally associated forebrain activation, i.e. it prevents illness-induced suppression of forebrain nuclei. These findings suggest that incoming neural signals regarding immune activation drive an active inhibition of forebrain regions that is initiated or mediated by the dorsal vagal complex. We intend to tease apart neurocircuitry that drives symptoms of behavioral depression by combining neuroanatomical tract tracers with immunohistochemical detection of neurotransmitter substances and c-Fos expression to identify the connections and neurochemical phenotypes of neurons driven by immune activation. We will then inactivate the neurons associated with the dorsal vagal complex to determine whether they contribute to the symptoms of illness-induced behavioral depression. The experiments designed for this proposal are directed toward developing a clearer picture of the structural and functional organization of brain regions driven by immune activation, and the neurochemical signals involved, that contribute to symptoms of behavioral depression. Findings from these experiments can provide a framework for the understanding and management of cognitive and affective sequelae to illness and chronic inflammatory disorders. An ultimate goal is to be able to predict which type or component of an immune or inflammatory stimulus may trigger anhedonic/depressive symptoms, and be able to predict effective treatments, based on the neurochemistry of the activated immunosensory pathways in the brain.